Muscular dystrophies are a diverse group of inherited disorders characterized by progressive muscle weakness and wasting (Bushby 2000; Cohn and Campbell, 2001). Duchenne muscular dystrophy (DMD) is the most common form of childhood muscular dystrophy and is caused by mutations in the dystrophin gene that lead to the complete absence of dystrophin in skeletal and cardiac muscle.
Efforts to identify the function of dystrophin have lead to the identification and characterization of the dystrophin-glycoprotein complex (DGC) in skeletal muscle. The DGC is a multimeric transmembrane protein complex in the sarcolemma. The proteins that comprise the DGC are the cytoplasmic proteins dystrophin, dystrobrevin and the syntrophins, and the sarcolemmal localized dystroglycans (α and β subunits), sarcoglycans (α, β, γ and δ subunits), and sarcospan (Campbell, 1995; Crosbie et al., 1997; Yang et al., 1994). Dystroglycan (DG) is a key component of the DGC (Ervasti et al., 1991) that is composed of α- and β-subunits which are post-translationally derived from a single mRNA encoded by the DAG1 gene (Ibraghimov-Beskrovnaya et al., 1992). In skeletal muscle α-dystroglycan is a highly glycosylated peripheral membrane protein that binds laminin-2 in the extracellular matrix, whereas β-dystroglycan is an integral membrane glycoprotein that anchors α-dystroglycan to the membrane and binds dystrophin intracellularly. Accumulated evidence indicates that the DGC provides a stable structural link between the actin cytoskeleton and the extracellular matrix in order to maintain the integrity of the muscle cell membrane during cycles of contraction and relaxation. The importance of the DGC in normal muscle function is underscored by discoveries that mutations in several components of the DGC give rise to distinct muscular dystrophies.
To date, there are no reports indicating that dystroglycan mutations cause muscular dystrophy in humans. However, dystroglycan structure and function are perturbed in many types of muscular dystrophy (Ibraghimov-Beskrovnaya et al., 1992; Duclos et al., 1998; Coral-Vazquez et al., 1999; Allamand et al., 2002). α-Dystroglycan is greatly reduced from the sarcolemma in muscle from patients with Duchenne muscular dystrophy and from the mdx mouse model. In limb-girdle muscular dystrophy (LGMD) patients, α- and β-dystroglycan are localized to the sarcolemma but α-dystroglycan is not appropriately anchored to the muscle plasma membrane. In both cases, perturbation of the dystroglycan complex results in a break in the structural connection between the sarcolemma and extracellular matrix.
Recently, a series of additional muscular dystrophies, dystroglycanopathies, have been identified. Emerging genetic data show that these diseases are linked to mutations in genes with homology to glycosyltransferases, enzymes that add or modify sugar structures on proteins. These diseases are typically characterized by severe muscular dystrophy including muscle necrosis and regeneration; some also exhibit a brain phenotype with neuronal migration defects as well as eye abnormalities and variable heart involvement. Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), LGMD2I, MDC1C, and MDC1D are all dystroglycanopathies. The fukutin gene in Fukuyama congenital muscular dystrophy was the first to be identified and encodes a protein with homology to glycoconjugate modifying enzymes (Kobayashi et al., 1998). Actual glycosyltransferase activity has been demonstrated for proteins mutated in muscle-eye-brain disease and Walker-Warburg syndrome, the O-mannosyl-β1, 2-N-acetylglucosaminyltransferase (POMGnT1) and Protein O-mannosyltransferase 1 and 2 (POMT1 and 2), respectively (Yoshida et al., 2001; Beltran-Valero de Bernabe. et al., 2002; Zhang et al., 2002; Manya et al., 2004; van Reeuwijk et al., 2005). LARGE, the gene mutated in Largemyd mice and MDC1D patients, encodes for a putative glycosyltransferase with two structurally distinct domains homologous to bacterial α-glycosyltransferase and mammalian β-1, 3-N-acetylglucosaminyltransferase (Peyrard et al., 1999; Grewal et al., 2001; Longman et al., 2003). Biochemical analysis of muscle biopsies has revealed a convergent role for these proteins in the glycosylation of α-dystroglycan, a process required for functional activity of this protein. The abnormal glycosylation of dystroglycan in disease disrupts the normal binding activity for each of its major extracellular matrix ligands in muscle and brain. Thus, disruption of dystroglycan ligand binding resulting in a loss of the functional link between the cytoskeleton and the extracellular matrix leads to severe muscular dystrophy (Michele et al., 2002).